Project Summary High-grade gliomas, such as glioblastoma and diffuse intrinsic pontine glioma (DIPG), represent the leading cause of brain cancer-related death for both adults and children. Among the most intractable human cancers, these tumors are quick to recur and nearly impossible to eliminate. A fundamental shift in our approach to glioma therapy is in dire need. My research group has recently discovered that gliomas grow in response to nervous system activity and further that gliomas exhibit a surprisingly profound dependency on these neuronal mechanisms. Our cellular and molecular work has led us to the startling realization that gliomas functionally integrate into electrically active neuronal circuits through bona fide neuron to glioma synapses, and the effects of neuron to glioma signaling may be amplified throughout the tumor via a network of recently described glioma to glioma gap junction-mediated connections. We hypothesize that this cooperative, interconnected network of glioma cells and neurons is fundamental to high-grade glioma progression and therapy resistance. Effective therapy for this lethal group of brain cancers may therefore require targeting not only molecular mechanisms of cell proliferation and survival, but also patterns of membrane depolarization and structural connections between cells. In order to study this, a shift from the predominant cellular/molecular perspective of cancer biology to a systems neuroscience approach is required. In the present proposal, we seek to apply the powerful next-generation tools of modern systems neuroscience together with patient-derived orthotopic xenograft models of high-grade gliomas to map, monitor and control the circuit dynamics of high-grade gliomas at progressive time points during the course of the disease. Optogenetic control of neuronal action potentials and of glioma membrane depolarizations together with live calcium imaging in awake, behaving mice will elucidate the functional significance of various temporal and spatial patterns of glioma circuit activity to glioma growth. Molecular interventions aimed at disassembling the various components of the neuronal- glioma network will discern the relative contribution of each and identify novel therapeutic targets. Ultimately, therapeutically modulating malignant circuit activity may prove transformative for high-grade glioma outcomes.!